Rheumatoid arthritis is a chronic systemic disease characterized by persistent intense immunologic activity. Recent data have suggested that CD4+ T cells play an essential role in propagating rheumatoid inflammation. Moreover, the data suggest that one abnormality in rheumatoid arthritis is the biased differentiation of IFN-gamma producing Th1 like memory T cells within the synovial compartment. Although synovial T cells are enriched in mature CD4+ CD27- T cells, they contain few, if any, IL-4 producing Th2-like memory cells. This suggests that rheumatoid inflammation might be characterized by an abnormality in the differentiation of IL-4 producing Th2-like cells such that there is persistent unregulated activity of IFN-gamma producing Th1-like memory cells. The proposed experiments will test this hypothesis. In addition, experiments will be carried out to delineate the regulatory events controlling the differentiation of Th l-like and Th2-like cells in patients with rheumatoid arthritis, determine whether abnormalities in the differentiation pathways of these effector T cell subsets are found in patients with rheumatoid arthritis, investigate the impact of synovial influences on these differentiative pathways, and determine whether unique clones of T cells differentiate into cytokine- producing Th1-like memory cells in the rheumatoid synovium. Finally, regulation of the differentiation of Th1 and Th2-like effector cells will be directly analyzed in vivo using rheumatoid synovial tissue engrafted into SCID mice. The specific aims will be: 1) to examine the capacity of CD4+ T cells from patients with RA to differentiate into IFN-gamma or IL-4 producing Th effector cells; 2) to determine whether features of the rheumatoid synovium influence the development of Th effector cells; and finally 3) to utilize an in vivo model of rheumatoid arthritis, the RA-SCID mouse, to examine the influences on the development of Th effector cells directly. It is anticipated that the information obtained should provide important new insights into the regulatory influences on the differentiation of CD4+ memory effector cells in man.